1. Field of the Invention
The present invention relates to certain polyoxometalate compounds, particularly amino acid salts of polyoxometalate compounds, and their use as antiviral agents. These agents can be advantageously used, for example, in the treatment of infection by retroviruses such as HIV (HTLV-III/LAV), which causes acquired immuno-deficiency syndrome (AIDS).
2. Background Information
AIDS was first recognized as early as 1979. The number of cases reported to the Centers for Disease Control (CDC) increased dramatically each year since then, and in 1982 the CDC declared AIDS a new epidemic. Between December 1987 and November 1988, over 32,000 new cases of AIDS were reported by the CDC (HIV/AIDS Surveillance Report, 1-16, December 1989). Over 3,000 new cases were reported in 1984 alone. The WHO estimates that at least 200,000 cases of the disease have occurred worldwide. It has also been estimated that approximately 5,000,000 people are infected today with HIV and at least 1,000,000 new cases of AIDS may be expected during the next 5 years.
In the United States, about 115,000 cases of AIDS have been reported to the U.S. Centers for Disease Control (CDC) to date. Nearly 28,000 were reported in 1987 alone. It has been predicted that in the United States 365,000 to 380,000 total cases will be reported by 1992. The CDC believes that 1 million to 1.5 million Americans are now infected with HIV. It is clear that the cost of the AIDS epidemic in terms of human lives is staggering, and the worst is yet to come.
Retroviruses were proposed as the causative agent of AIDS. Two such retroviruses now known to cause AIDS have been identified and isolated: LAV (lymphadenopathy-associated virus) and HTLV-III (human T-cell leukemia virus). It was later determined that LAV and HTLV-III are identical. Recently, human immunodeficiency virus type 1 (HIV) has emerged as a preferred name for the virus responsible for AIDS. Antibodies to HIV are present in over 80% of patients diagnosed as having AIDS or pre-AIDS syndrome, and it has also been found with high frequency in identified risk groups.
There is considerable difficulty in diagnosing the risk of development of AIDS. AIDS is known to eventually develop in almost all of the individuals infected with HIV.
A patient is generally diagnosed as having AlDS when a previously healthy adult with an intact immune system acquires impaired T-cell immunity. The impaired immunity usually appears over a period of 18 months to 3 years. As a result of this impaired immunity, the patient becomes susceptible to opportunistic infections, various types of cancers such as Kaposi's sarcoma, and other disorders associated with reduced functioning of the immune system.
Another condition associated with HIV is AIDS-related complex, or ARC. This condition can lead to AIDS in some cases.
No treatment capable of preventing the disease or significantly reversing the immunodeficiency of AIDS or ARC is currently available. All patients with opportunistic infections and approximately half of all patients with Kaposi's sarcoma have died within two years of diagnosis. Attempts at reviving the immune systems in patients with AIDS have been unsuccessful.
It has been reported that 3′-azido-3′-deoxythymidine (AZT) is an antiviral agent that inhibits the infectivity and cytopathic effect of HIV-1 in vitro and prolongs life in vivo (see Mitsuya et al, Proc. Natl. Acad. Sci. USA 82, 7096-100, 1985; and Fischl et al, New Engl. J. Med. 317, 185-191, 1987). However, this compound exhibits reversible bone marrow toxicity in a clinical setting (see Yarchoan et al, Lancet 575-580, 1986; Richman et al, New Engl. J. Med. 317, 192-197, 1987). In addition, the development of resistance to AZT is a drawback to its use as an antiviral agent (see Larder et al, Science 243, 1731-1734, 1989). AZT was originally synthesized by Horwitz et al, J. Org. Chem. 29, 2076-2078, 1964. Its activity against Friend leukemia virus (a retrovirus) was reported as early as 1973 (see Ostertage et al, Proc. Natl. Acad. Sci. USA 71, 4980-4985, 1974, and Krieg et al, Exptl. Cell. Res. 116, 21-29, 1978, and references cited therein). The compounds of this invention are structurally unrelated to AZT.
U.S. Pat. No. 4,681,933 describes certain 2′,3′-dideoxy-5-substituted uridines and related compounds as antiviral agents. Structurally, these compounds are similar to AZT, and are remote from those of the present invention.
U.S. Pat. No. 4,759,929 discloses a method of treating HIV-1 infection in warm-blooded animals which involves treatment with a salt of 9-antimonio-III-21-tungsten-VI-sodate, (NH4+)17H+[NaSb9W21O86] (also known as HPA-23). This compound is a polyoxometalate, but it is compositionally different from the compounds of the present invention. Moreover, there are disadvantages associated with this drug, such as: (1) it induces thrombocytopenia and displays, in general, a high toxicity to human bone marrow cells, and (2) it must be taken intravenously as it degrades at pH<4.
Polyoxometalate compounds have also been discovered to have anticoagulant activity. French Patent 2,587,214 is directed to anticoagulant tungstic heteropoly anions for use in vivo and in vitro to prevent blood coagulation.
Polyoxometalates or polyoxoanions are condensed oligomeric aggregates of metal and oxygen atoms that occur in two generic forms: those that contain only these atoms (isopolyoxo anions, isopoly compounds or isos), and those that contain one or more “heteroatoms” in addition to the metal and oxygen atoms (heteropoly anions, heteropoly compounds or heteros). The heteroatoms in the latter class of complexes can be either main group ions, such as Si4+ [as in the silicotungstate, (SiW12O40)4−], P5+ [as in the Dawson tungstate, (P2W18O62)6−], or transition group ions, such as Fe3+ or Co2+.
Polyoxometalates have been known for over a century, but only recently has interest in these materials increased. To some degree, this is due to the fact that these materials have become more chemically well defined. In addition, since 1977, the polyoxometalates, and particularly the heteropoly compounds or heteropoly acids, have received increasing attention as reagents or catalysts for redox processes involving organic substrates.
In spite of the known agents for treatment of AIDS, there continues to remain a need for new and effective methods for treatment of retroviral infections, particularly HIV infection, including AIDS and AIDS related complex (ARC). It was in this context that the present invention was accomplished.